ABSTRACT Opioid addiction is a chronically relapsing disorder, and chronic pain is a highly prevalent condition that is thought to be a potential trigger for drug relapse. A major contributor to relapse is that drug-related stimuli and environments have the ability to powerfully elicit cravings and trigger relapse. Thus, a goal of current treatment plans is to reduce craving evoked by drug-related stimuli and stressors, such as chronic pain. Psychosocial enrichment has been shown to diminish drug craving and activation of the medial prefrontal cortex (mPFC) in response to drug-related stimuli, and in a rodent model, environmental enrichment (EE) also reduces drug seeking and the ability of drug-related stimuli to activate the mPFC. Despite the robust ability of environmental factors to reduce behavioral and physiological responses to drug stimuli, the mechanisms of this phenomenon are not known. It is possible that EE directly modulates a specific ensemble of neurons that is engaged by exposure to a previous opioid-taking environment. One such drug-seeking ensemble resides in the mPFC, a region where enrichment reduces drug stimuli-elicited activity. Our studies will focus on these ensemble neurons to determine if EE affects their ability to become re-activated by exposure to a drug environment, if EE alters oxycodone-associated plasticity in these neurons, and if chronic neuropathic pain increases opioid seeking and activity of neurons within the mPFC drug seeking ensemble.